Comparison of high- and low-molecular-weight sensitizing agents causing occupational asthma: an evidence-based insight.

INTRODUCTION: The many substances used at the workplace that can cause sensitizer-induced occupational asthma are conventionally categorized into high-molecular-weight (HMW) agents and low-molecular-weight (LMW) agents, implying implicitly that these two categories of agents are associated with distinct phenotypic profiles and pathophysiological mechanisms. AREAS COVERED: The authors conducted an evidence-based review of available data in order to identify the similarities and differences between HMW and LMW sensitizing agents. EXPERT OPINION: Compared with LMW agents, HMW agents are associated with a few distinct clinical features (i.e. concomitant work-related rhinitis, incidence of immediate asthmatic reactions and increase in fractional exhaled nitric oxide upon exposure) and risk factors (i.e. atopy and smoking). However, some LMW agents may exhibit 'HMW-like' phenotypic characteristics, indicating that LMW agents are a heterogeneous group of agents and that pooling them into a single group may be misleading. Regardless of the presence of detectable specific IgE antibodies, both HMW and LMW agents are associated with a mixed Th1/Th2 immune response and a predominantly eosinophilic pattern of airway inflammation. Large-scale multicenter studies are needed that use objective diagnostic criteria and assessment of airway inflammatory biomarkers to identify the pathobiological pathways involved in OA caused by the various non-protein agents.

An Official American Thoracic Society Workshop Report: Presentations and Discussion of the Sixth Jack Pepys Workshop on Asthma in the Workplace.

The Sixth Jack Pepys Workshop on Asthma in the Workplace focused on six key themes regarding the recognition and assessment of work-related asthma and airway diseases: (1) cleaning agents and disinfectants (including in swimming pools) as irritants and sensitizers: how to evaluate types of bronchial reactions and reduce risks; (2) population-based studies of occupational obstructive diseases: use of databanks, advantages and pitfalls, what strategies to deal with biases and confounding?; (3) damp environments, dilapidated buildings, recycling processes, and molds, an increasing problem: mechanisms, how to assess causality and diagnosis; (4) diagnosis of occupational asthma and rhinitis: how useful are recombinant allergens (component-resolved diagnosis), metabolomics, and other new tests?; (5) how does exposure to gas, dust, and fumes enhance sensitization and asthma?; and (6) how to determine probability of occupational causality in chronic obstructive pulmonary disease: epidemiological and clinical, confirmation, and compensation aspects. A summary of the presentations and discussion is provided in this proceedings document. Increased knowledge has been gained in each topic over the past few years, but there remain aspects of controversy and uncertainty requiring further research.

An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma.

The fifth Jack Pepys Workshop on Asthma in the Workplace focused on the similarities and differences of work-related asthma (WRA) and non-work-related asthma (non-WRA). WRA includes occupational asthma (OA) and work-exacerbated asthma (WEA). There are few biological differences in the mechanisms of sensitization to environmental and occupational allergens. Non-WRA and OA, when due to high-molecular-weight agents, are both IgE mediated; it is uncertain whether OA due to low-molecular-weight agents is also IgE mediated. Risk factors for OA include female sex, a history of upper airway symptoms, and a history of bronchial hyperresponsiveness. Atopy is a risk factor for OA due to high-molecular-weight agents, and exposure to cleaning agents is a risk factor for both OA and non-WRA. WEA is important among workers with preexisting asthma and may overlap with irritant-induced asthma, a type of OA. Induced sputum cytology can confirm airway inflammation, but specific inhalation challenge is the reference standard diagnostic test. Inhalation challenges are relatively safe, with the most severe reactions occurring with low-molecular-weight agents. Indirect health care costs account for about 50% of total asthma costs. Workers with poor asthma control (WRA or non-WRA) are less likely to be employed. Income loss is a major contributor to the indirect costs of WRA. Overall, asthma outcomes probably are worse for adult-onset than for childhood-onset asthma but better for OA than adult-onset non-WRA. Important aspects of management of OA are rapid and proper confirmation of the diagnosis and reduction of exposure to sensitizers or irritants at work and home.

Specific inhalation challenge with flour induced release of brain-derived neurotrophic factor in nasal fluid.

BACKGROUND: Neurotrophins may play a role in the pathophysiology of allergic occupational rhinitis (OR). We sought to investigate whether an immediate allergic reaction that induces nasal inflammation is also able to induce changes in levels of brain-derived neurotrophic factor (BDNF) in nasal lavage (NAL) fluid from patients with allergic OR. METHODS: Ten patients sensitized to flour underwent control and active specific inhalation challenge (SIC) on consecutive days. Nasal response to SIC was monitored with acoustic rhinometry and symptoms recording. NAL was performed before and 30 minutes, 6 hours, and 24 hours after control and active challenge for the assessment of levels of BDNF and inflammatory cells in NAL fluid. RESULTS: In contrast to control day, flour challenge induced immediate clinical reactions in all subjects. After flour challenge, a significant increase in levels of BDNF in NAL fluid was observed at 6 hours after challenge (p < 0.05). Also, a significant increase in the number of eosinophils in NAL fluid at 30 minutes (p < 0.01), 6 hours (p < 0.01), and 24 hours (p = 0.05) postchallenge was observed. Also, levels of BDNF in NAL fluid were significantly higher at 30 minutes after flour challenge (p = 0.02) in comparison to levels on the control day at the same postchallenge time. A marginally significant positive correlation between BDNF levels and eosinophil counts at 30 minutes (r = 0.60, p = 0.06) and at 6 hours (r = 0.50, p = 0.08) after flour challenge was noted. CONCLUSION: We showed that BDNF is released in nasal fluid after SIC with flour. Results support the suggestion that neurotrophins may play a role in the pathogenesis of allergic OR.

An official American Thoracic Society proceedings: work-related asthma and airway diseases. Presentations and discussion from the Fourth Jack Pepys Workshop on Asthma in the Workplace.

Work-related asthma is a common occupational lung disease. The scope of the Fourth Jack Pepys Workshop that was held in May 2010 went beyond asthma to include discussion of other occupational airway diseases, in particular occupationally related chronic obstructive pulmonary disease (COPD) and bronchiolitis. Aspects explored included public health considerations, environmental aspects, outcome after diagnosis, prevention and surveillance, and other work-related obstructive airway diseases. Consistent methods are needed to accurately estimate the comparative burden of occupation-related airway diseases among different countries. Challenges to accomplishing this include variability in health care delivery, compensation systems, cultural contexts, and social structures. These factors can affect disease estimates, while heterogeneity in occupations and workplace exposures can affect the underlying true prevalence of morbidity. Consideration of the working environment included discussion of practical methods of limiting exposure to respiratory sensitizers, methods to predict new sensitizers before introduction into workplaces, the role of legislated exposure limits, and models to estimate relative validity of various ameliorative measures when complete avoidance of the sensitizer is not feasible. Other strategies discussed included medical surveillance measures and education, especially for young individuals with asthma and new workers about to enter the workforce. Medical outcomes after development of sensitizer-induced occupational asthma are best following earlier diagnosis and removal from further exposure, but a subset may be able to continue working safely provided that exposure is reduced under close follow-up monitoring. It was recognized that occupationally related COPD is common but underappreciated, deserving further study and prevention efforts.

Long-term socioprofessional and psychological status in workers investigated for occupational asthma in quebec.

OBJECTIVE: To compare the long-term status of workers with occupational asthma (OA) with those of subjects with work-exacerbated asthma (WEA) and nonasthmatic (NA) workers. METHODS: We contacted 179 subjects investigated for suspected OA at Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada, from 1997 to 2007. Participants completed questionnaires on psychological and functional status, followed by a telephone interview about socioprofessional outcomes and health care utilization. RESULTS: The OA workers are more likely to have been removed from the workplace than the WEA workers. The health-related quality of life of all workers was still impaired. A high prevalence of psychiatric disorders was found among OA and WEA workers. Compared with WEA and OA workers, the NA group showed a higher rate of physician consultations for all causes. CONCLUSIONS: Regardless of the diagnosis they received, these workers need to benefit from psychosocial support in the period after investigation for suspicion of OA.

Prospective outcome assessment of occupational rhinitis after removal from exposure.

OBJECTIVE: To conduct a prospective evaluation of clinical and quality of life (QOL) outcomes of occupational rhinitis (OR) after cessation of exposure. METHODS: We assessed changes in nasal symptoms, disease-specific QOL, nasal patency, and nasal inflammation in 20 subjects with confirmed OR. Olfactory function was assessed cross-sectionally at follow-up. RESULTS: At follow-up, a significant decrease in the number of nasal symptoms and a significant improvement in QOL were observed. There were no significant differences in nasal patency outcomes. A not significant decrease in neutrophils number in nasal fluid and a significant decrease in macrophages were observed. As a group, study subjects showed a mild olfactory dysfunction at follow-up. CONCLUSIONS: We showed that cessation of exposure to causal agent improved QOL in patients with OR, leading to relief of rhinitis-associated symptoms and improvement in well-being.

Prevalence of psychiatric disorders among patients investigated for occupational asthma: an overlooked differential diagnosis?

RATIONALE: Up to one-third of patients assessed for occupational asthma (OA) do not receive a diagnosis of OA or any other medical disorder. Although several differential diagnoses are considered (e.g., rhinitis, chronic obstructive pulmonary disease), psychiatric disorders (many with somatic complaints that mimic asthma) are rarely considered or assessed. OBJECTIVES: To assess the prevalence of psychiatric disorders (mood and anxiety disorders and hypochondriasis) in patients suspected of having OA, and whether psychiatric morbidity increases the risk of not receiving any medical diagnosis. METHODS: A total of 219 consecutive patients (57% male; mean age, 41.8 ± 11.1 yr) underwent sociodemographic and medical history interviews on the control or specific inhalation testing day of their OA evaluation. The Primary Care Evaluation of Mental Disorders was used to assess mood and anxiety disorders, and the Whiteley Hypochondriasis Index was used to assess hypochondriasis. MEASUREMENTS AND MAIN RESULTS: A total of 26% (n = 50) of patients had OA; 25% (n = 48) had asthma or work-exacerbated asthma; 14% (n = 28) had another inflammatory disorder; 13% (n = 26) had a noninflammatory disorder; and 22% (n = 44) did not receive any medical diagnosis. A total of 34% (n = 67) of patients had a psychiatric disorder: mood and anxiety disorders affected 29% (n = 57) and 24% (n = 46) of the sample, respectively, and 7% (n = 12) had scores on the Whiteley Hypochondriasis Index indicating hypochondriasis. Hypochondriasis, but not mood or anxiety disorders, was associated with an increased risk of not receiving any medical diagnosis (adjusted odds ratio, 3.92; 95% confidence interval, 1.18-13.05; P = 0.026). CONCLUSIONS: Psychiatric morbidity is common in this population, and hypochondriasis may account for a significant proportion of the "undiagnosable" cases of patients who present for evaluation of OA.

CTNNA3 (α-catenin) gene variants are associated with diisocyanate asthma: a replication study in a Caucasian worker population.

Recently, a genome-wide association study (GWAS) conducted in Korean subjects identified four CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, rs1786929, and rs4378283) associated with diisocyanate-induced occupational asthma (DA). The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions. We conducted a candidate gene association study to replicate these findings in Caucasian workers. Genotyping was performed on DNA using a 5' nuclease PCR assay collected from 410 diisocyanate-exposed and predominantly Canadian workers including 132 workers with DA confirmed by a specific inhalation challenge (DA+); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA-); and 147 hexamethylene diisocyanate-exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs (but not rs4378283 and rs1786929) were significantly associated with DA+ when compared with AWs but not in comparison with DA- workers (p ≤ 0.05). After adjusting for potentially confounding variables of age, smoking status, and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs (OR = 9.05 [95% CI: 1.69, 48.54] and OR = 6.82 [95% CI: 1.65, 28.24], respectively). In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA. These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of catenins in the disease process.

Matrix metalloproteinase-9 increases in the sputum from allergic occupational asthma patients after specific inhalation challenge.

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the pathogenesis of asthma. MMP-9 increases in the sputum of asthmatic patients after bronchial challenge with common allergens. We sought to assess whether a high-molecular-weight occupational allergen was able to induce changes in MMP-9 as well as in other MMPs and TIMPs in subjects with occupational asthma. METHODS: Ten patients underwent specific inhalation challenge (SIC) on 2 consecutive days. We monitored changes in lung function by measuring FEV(1) for 7 h. Induced sputum test was performed at 6 h after sham and flour challenge. The total and differential cell counts were analyzed. Levels of MMPs (specifically MMP-2, MMP-7, MMP-9 and MMP-13) were measured using Fluorokine® MultiAnalyte Profiling kits and a Luminex® Bioanalyzer, while levels of TIMP-1 and TIMP-2 were measured by ELISA. RESULTS: Flour challenge increased the percentage of eosinophils in sputum samples. Asthmatic reactions induced by flour were associated with a significant increase in the sputum level of MMP-9 (p = 0.05), but not in the levels of MMP-2, MMP-7, MMP-13, TIMP-1 and TIMP-2. Sputum levels of MMP-9 measured after flour challenge were nearly significantly correlated (r = 0.67; p = 0.06) with the maximal fall in FEV(1) observed during the asthmatic reaction, but they did not correlate with the number of neutrophils (r = 0.18; p = 0.7) and eosinophils (r = 0.55; p = 0.2). CONCLUSIONS: This study showed that MMP-9 increases in sputum samples from sensitized occupational asthma patients after SIC with flour.

Genetic variants in antioxidant genes are associated with diisocyanate-induced asthma.

Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95); symptomatic diisocyanate workers with a negative SIC (DA(-), n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5'-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA(+) and DA(-) groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044, respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the second model comparing DA(+) and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in nasal lavage after an inhalation challenge with flour.

OBJECTIVES/HYPOTHESIS: The existence of nasal mucosa remodeling in allergic rhinitis is controversial. Few data are available on the dynamics of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in nasal fluid after an allergen challenge. We examined whether an immediate allergic reaction that induces nasal congestion and inflammation is able to also induce changes in remodeling parameters in nasal fluid. STUDY DESIGN: Controlled experimental study. METHODS: Ten patients with allergic occupational rhinitis due to flour underwent a control and active inhalation challenge with serial monitoring of nasal congestion and nasal symptoms with acoustic rhinometry and a visual analogue scale. Levels of remodeling markers (MMP-2, MMP-7, MMP-9, MMP-13, TIMP-1, TIMP-2) and inflammatory cells in nasal fluid were measured before the challenge and at 30 minutes, 6 hours, and 24 hours following the challenge. RESULTS: In contrast to the control challenge, the flour challenge induced nasal symptoms and significant decreases in nasal volume in all subjects. After the flour challenge, a significant increase in nasal levels of TIMP-2 and a nonsignificant increase in TIMP-1 levels were observed, whereas no significant changes in nasal levels of MMPs were documented. CONCLUSIONS: This study showed that after an inhalation challenge with an occupational allergen, the nasal mucosa displayed an imbalance in favor of TIMPs enzymes activity as compared to MMPs enzymes activity, represented in an increase in nasal levels of TIMP-2 during the course of the early reaction following the allergen challenge.

Definitions and classification of work-related asthma.

The workplace can trigger or induce asthma and cause the onset of different types of work-related asthma (WRA). Based on current knowledge of clinical features, pathophysiologic mechanisms, and evidence supporting a causal relationship, the following conditions should be distinguished in the spectrum of WRA: (1) immunologic occupational asthma (OA), (2) nonimmunologic OA, (3) work-exacerbated asthma, and (4) variant syndromes, including eosinophilic bronchitis, potroom asthma, and asthmalike disorders caused by organic dusts. The rationale, issues, and controversies relating to this approach are critically reviewed to stimulate the development of a consensus on operational definitions of the various phenotypes of WRA.

Identification of clinically significant psychological distress and psychiatric morbidity by examining quality of life in subjects with occupational asthma.

BACKGROUND: The Juniper Asthma Specific Quality of Life Questionnaire (AQLQ(S)) is a questionnaire that allows measurement of disease specific quality of life. We wanted to examine correlations between the (AQLQ(S)) general and different subscale scores and both psychiatric morbidity and levels of psychological distress in individuals with occupational asthma (OA) and to determine if results in the emotional function subscale allow identification of individuals with clinically significant psychological distress or current psychiatric disorders. METHODS: This was a cross-sectional study of individuals with OA who were assessed during a re-evaluation for permanent disability, after they were no longer exposed to the sensitizing agent. Patients underwent a general sociodemographic and medical history evaluation, a brief psychiatric interview (Primary Care Evaluation of Mental Disorders, PRIME-MD) and completed a battery of questionnaires including the AQLQ(S), the St-Georges Respiratory Questionnaire (SGRQ), and the Psychiatric Symptom Index (PSI). RESULTS: There was good internal consistency (Cronbach alpha = 0.936 for the AQLQ(S) total score) and construct validity for the AQLQ(S) (Spearman rho = -0.693 for the SGRQ symptom score and rho = -0.650 for the asthma severity score). There were medium to large correlations between the total score of the AQLQ(S) and the SGRQ symptom score (r = -.693), and PSI total (r = -.619) and subscale scores (including depression, r = -.419; anxiety, r = -.664; anger, r = -.367; cognitive disturbances, r = -.419). A cut-off of 5.1 on the AQLQ(S) emotional function subscale (where 0 = high impairment and 7 = no impairment) had the best discriminative value to distinguish individuals with or without clinically significant psychiatric distress according to the PSI, and a cut-off of 4.7 best distinguished individuals with or without a current psychiatric disorder according to the PRIME-MD. CONCLUSIONS: Impaired quality of life is associated with psychological distress and psychiatric disorders in individuals with OA. Findings suggest that the AQLQ(S) questionnaire may be used to identify patients with potentially clinically significant levels of psychological distress.